11-(4-Pyridylalkyl-piperazino)-dibenzothiazepines

ABSTRACT

Piperazine derivatives having the formula   WHEREIN EACH OF X1 and X2 is H, Cl, CH3, CH3O or CF3; Y is thienyl, furyl, pyridyl, thiazolyl, phenyl or substituted phenyl, in which the phenyl substituents are 1 or 2 groups selected from the group consisting of Cl, CH3, CH3O and CF3; Z is -S-, -SO2-, O-, -NR- or -SO2-NR-, in which R is an alkyl group having from 1 to 4 carbon atoms; n is 2 or 3; and m is 0, 1 or 2; and the pharmaceutically acceptable acid addition salts thereof are disclosed. The piperazine derivatives and their pharmaceutically acceptable addition salts are useful as anti-allergics, psychotropics and analgesics.

United States Patent Nakanishi et a1.

1 1-(4-PYR1DYLALKYL-PIPERAZINO)- DIBENZOTHIAZEPINES Inventors: Michio Nakanishi, Oita; Tomohiko Munakata, Fujuoka; Yutaka Maruyama, Tokyo; Shinro Setoguchi, Fukuoka, all of Japan Yoshitomi Pharmaceutical Industry, Ltd., Osaka, Japan Filed: Mar. 9, 1973 Appl. No.: 339,794

Related U.S. Application Data Division of Ser. No. 60,139, July 31, 1970, Pat. No. 3,761,481.

Assignee:

Foreign Application Priority Data July 31, 1969 Japan 44-60651 Sept. 25, 1969 Japan 44-76775 Oct. 2, 1969 Japan 44-79478 U.S. Cl 260/268 TR; 260/239 DD; 260/327 B; 260/333; 260/47 D;

Int. Cl C07d 51/70 Field of Search 260/268 TR, 268 H References Cited UNITED STATES PATENTS Primary ExaminerDonald G. Daus Assistant ExaminerJose Tovar Attorney, Agent, or FirmSughrue, Rothwell, Mion, Zinn & Macpeak [57] ABSTRACT Piperazine derivatives having the formula /CH2-C1-12\ N Z /\(CHZ)n/ m -C wherein each of X and X is H, Cl, CH CH O or C1 Y is thienyl, furyl, pyridyl, thiazolyl, phenyl or substituted phenyl, in which the phenyl substituents are 1 or 2 groups selected from the group consisting of C1, CH C11 0 and CF Z is -S, SO O, NR or -SO NR, in which R is an alkyl group having from 1 to 4 carbon atoms; n is 2 or 3; and m is 0, 1 or 2; and the pharmaceutically acceptable acid addition salts thereof are disclosed. The piperazine derivatives and their pharmaceutically acceptable addition salts are useful as anti-allergics, psychotropics and analgesics.

9 Claims, N0 Drawings 1 11-(4-PYRIDYLALKYL-PIPERAZINO)- DIBENZOTHIAZEPINES CROSS-REFERENCE TO RELATED APPLICATIONS FIELD OF THE INVENTION This invention relates to novel and therapeutically valuable piperazine derivatives.

SUMMARY OF THE INVENTION The novel piperazine derivatives of this invention are compounds having the following general formula [I] wherein X and X each is selected from the group consisting of H, C], CH CH O and CF;,; wherein Y is selected from the group consisting ofa thienyl, a furyl, a pyridyl, a thiazolyl, a phenyl and a monoor disubstituted phenyl group, in which the substituents are selected from the group consisting of Cl, CH CH O and CF wherein Z is selected from the group consisting of S, SO O, NR- or SO- NR, in which R is an alkyl group having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl and butyl; wherein n is an integer of 2 or 3; and wherein m is an integer 0, 1 or 2, and the pharmaceutically acceptable acid addition salts thereof.

DETAILED DESCRIPTION OF THE INVENTION reacting a compound having the formula with a compound having the formula [Ill] 65 wherein X X Y, Z and m have the same meanings as described above, and one of P and Q is a group having the formula wherein n has the same meaning as described above and M is an H atom or an alkali metal atom, such as Na or K, and the other is a reactive residue such as a halogen atom (for example, Cl, Br or I), an organic sulfonyloxy group (for example, methylsulfonyloxy, phenylsulfonyloxy or p-tolylsulfonyloxy), or a lower alkylthio group or an aralkylthio group (for example, methylthio, benzylthio or p-nitrobenzylthio).

The reaction is usually carried out in an inert solvent, such as benzene, toluene, xylene, dimethyl ether, diethyl ether, dioxane, tetrahydrofuran, pentane, hexane, heptane, petroleum ether, ligroin, methanol, ethanol,

20 isopropanol, methyl acetate, ethyl acetate, isopropyl acetate, dimethylforrnamide or dimethyl sulfoxide, at from room temperature (20-30C) to the boiling point of the solvent employed for from several hours to several tens of hours. The reaction can also be carried out in the presence of an acid acceptor, such as potassium carbonate, sodium carbonate, triethylamine or pyridine.

The starting compounds having the formula [II] or [III] wherein M is an alkali metal atom can be produced by treating a compound having the formula [II] or [III] wherein M is H with an alkali metal compound, such as metallic sodium, sodium hydride, potassium hydride, sodium amide, potassium amide or lithium amide.

The compounds having the formula [I] can be converted in a conventional manner into the corresponding acid addition salts by treatment with various inorganic and organic acids, for example, hydrochloric, sulfuric, nitric, hydrobromic, oxalic, maleic, fumaric, tartaric, citric, o-(p-hydroxy-benzoyl)benzoic acid, phenolphthalin and the like.

Among the starting compounds [II] and [III] new compounds can be produced according to the following reaction schemes, for example [II], in which P is Cl 3 4 z CH3OO NHCO 1 2 1 v x X x X2 heat a I N= c- POCl 1 2 [III], in which Q is H, m and n are both 2, and Y is the intraperitoneal administration of the test compyridyl The compounds having the formula [I] and their pharmaceutically acceptable acid addition salts have various pharmacological properties, such as inhibition of edema, suppression of spontaneous motility, reserpine potentiation and analgesic action as shown, for example, by the following tests. The tests were carried out according to the following procedure:

1. Inhibition of serotonin edema and dextran edema was measured using the method described by CA. Winter in Proceedings of the Society for Experimental Biology and Medicine, 1 l 1, 544 ff. (1962). The procedure used was as follows:

0.05 ml of an aqueous solution of serotonin creatinine sulfate (10) or 0.05 ml of a 2% aqueous solution of dextran was injected subcutaneously into a rats paw (Donryu rat, male; about 150 g), each group consisting of five animals. The test compound was suspended in a 1% aqueous Polysorbate 80 solution and the suspension (5 ml/200 g of body weight) was administered orally one hour before the injection of the inflammation-causing substance. The volume of the paw was measured on hour after the injection of the serotonin or three hours after the injection of the dextran. The

ED shows the effective dose inhibiting edema induced by the inflammation-causing substance to 50%.

The results obtained are shown in Table l.

2. Supression of spontaneous motility was measured using the Photocell method described by RB. Dews in British Journal of Pharmacology, 8, 46 ff. (1953). The procedure used was as follows:

Male mice of the dd-strain weighing 20-25 g were gregariously placed in a box 20 X 40 X 20 cm, each group consisting of five animals. Forty minutes after the cumulative number of writhings pound, the frequency of movement was counted for 20 ZG Q i j N eduction 7 minutes, and the frequency was regarded as the motility. The ED shows the effective dose suppressing the spontaneous motility to 50%.

The results obtained are shown in Table 2.

3. Reserpine potentiation was measured using the method described by MD. Aceto in Toxicology and Applied Pharmacology, 7,329 ff. (1965). The procedure used was as follows:

Thirty minutes after the subcutaneous administration of the test compound to female mice (dd-strain mice weighing 20-25 g, each group consisting of four animals), reserpine (10 mg/kg of body weight) was injected intraperitoneally. The degree of blepharoptosis of both eyes was observed 15, 60, and minutes after the administration of the reserpine. The PD shows the effective dose potentiating the effect of reserpine by 30% 15 minutes after the administration of reserpine.

The results obtained are shown in Table 2.

4. Analgesic activity was measured using the method described by L. C. Hendershot in Journal of Pharmacology and Experimental Therapeutics, 125, 237 ff. (1959). The procedure used was as follows:

A 0.02% aqueous solution of benzoquinone (0.2 ml/20 g of body weight) was injected intraperitoneally into the mice weighing about 20 g, each group consisting of six animals. The test compound was suspended in a 1% aqueous Polysorbate 80 solution and the suspension (0.1 ml/lO g body weight) was administered orally one hour before the injection of the benzoquinone. The ED shows the effective dose diminishing for 30 minutes to Serotonin Edema Dextran Edema Compound ED (mg/kg) ED (mg/kg) A 1.3 1.4 B 1.0 1.2 C 2.7 3.0 D 2.2 1.6 E 1.0 1.6 F 1.0 1.8 G 0.8 1.8 H 1.3 3.8 J 0.13 2.0 K 0.18 2.5 L 3.0 3.0 M 0.5 2.0 N 0.6 1.3 O 0.9 3.0 P 0.8 0.5 Q 0.16 0.8

TABLE 2 Com- Supression of Spontaneous Reserpine Potentiation pound Motility ED (mg/kg) PD (mg/kg) 0 1.25 2.5 0.63 1.25 P 0.08 0.16 0.16 0.31 O 0.04 0.08 0.31 0.63 R 1.25 .5 0.31 0.63

TABLE 3 Analgesic Activity Compound ED (mg/kg) D 4.8 E 2.2 G 9 H 5 .I 9.5 K 5 N 2.1 O 7.6 P 3.2 Q 0.94 R 6 S 5.8 T 4.2

In the above tables, the compounds designated by letters A to T are as follows:

A11 l-[4-(2-Thenyl)- l -piperazinyl]- dibenzo[b,f][ 1,4]thiazepine dihydrochloride 0.5 hydrate B: 1 1-(4-Benzyll -piperazinyl)- dibenzo[b,f][1,4]thiazepine dihydrochloride monohydrate C: l l-[4-(p-Chlorobenzyl)-1-piperazinyl1- dibenzo[b,f][ 1,4]thiazepine dihydrochloride monohydrate D: 1 l-(4-Phenethyl-1-piperazinyl)- dibenzo[b,f][ 1,4]thiazepine dihydrochloride monohydrate E:2-Chl0ro-1 1-(4-phenethyll-piperazinyl dibenzo[b,f][ l,4]thiazepine dihydrochloride dihydrate F:2-Chloro-l l-[4(2-thenyl)-l-piperazinyl]- dibenzo[b,f][ 1,4]thiazepine Hydrochloride G: l l-( 4-Benzyll -piperazinyl)-2-chlorodibenzo[b,f][ 1,4]thiazepine Hydrochloride I-I:l l-[4-(2-Pyridylmethyl)- l -piperazinyl]- dibenzo[b,f][1,4]thiazepine trihydrochloride 1.5 hydrate J12-Chloro-l l-[4-(2-pyridylmethyl)- l -piperazinyl]- dibenzo[b,f][ 1,4]oxazepine trihydrochloride 0.5 hydrate Kz2-Chloro-l 1-[4-(2-(4-pyridyl)ethyl)-1- piperazinyl]dibenzo[b,f][ 1,4]-oxazepine chloride monohydrate Lzl 1-[4-(2-(4-Pyridyl)ethyl)- l -piperazinyl]- dibenzo[b,f][1,4]thiazepine trihydrochloride 0.5 hydrate Mz2-Chloro-1 l-[4-(2-pyridylmethyl)-1-piperazinyl]- dibenzo[b,f][1,4]thiazepine trihydrochloride 0.5 hydrate N:2-Chloro-l l-[4-(2(4-pyridylethyl)-lpiperazinyl]-dibenzo[b,f][ l ,4]-thiazepine chloride monohydrate Ozl l-[4-(2-(2-Pyridyl)ethyl)- l -piperazinyl]-dibenzo[b,f][ 1,4]oxazepine trihydrochloride monohydrate trihydrotrihydro piperazinyl]-dibenzo[b,f][ l ,4]-thiazepine trihydrochloride monohydrate Qz2-chloro-l l-[4-(2-(2-pyridyl)ethyl)-lpiperazinyl]-dibenzo[b,f][ l ,4]-oxazepine trihydrochloride monohydrate R: 1 l-[4-(2-(2-Pyridyl)ethyl)-l-piperazinyl]- dibenzo[b,f][1,4]thiazepine trihydrochloride drate S21 l-(4-Phenethyl-1-piperazinyl)-dibenzo[b,f][ l 4]oxazepine dihydrochloride 1.5 hydrate Tz2-Chloro-l1-[4-(3-pyridylmethyl)-l-piperazinyl1- dibenzo[b,f][l,4]oxazepine trihydrochloride 0.5 hydrate In view of various tests including those mentioned above, the compounds of the present invention having the general formula [I] and the pharmaceutically acceptable acid addition salts thereof can be administered safely as antiallergic agents for the treatment of various types of allergic diseases such as asthma, urticaria, eczema, hay fever, allergic migraine and pruitus cutaneous, as analgesics for the treatment of pains in post-operation, various kinds of carcinoma, delivery, myocardiac infarction, gastric and duodenal ulcer and the like, and as psychotropic agents for the treatment of schizophrenia, mania, psychroneuroses and the like, in the form of a pharmaceutical preparation with a suitable and conventional carrier or adjuvant, administrable orally or by way of injection without harm to the host.

The pharmaceutical preparations can take any conventional form such as tablets, capsules, granules, powders, syrups, injectable solutions, and the like.

The following are illustrative examples of formulations to be administered when the compounds having the formula [I] and their acid addition salts are administered for the above pharmaceutical purposes.

(a) 10 mg tablets are prepared from the following composition:

Compound having the General Formula [I] 10 mg Lactose mg Starch 38 mg Methyl Cellulose 1 mg Magnesium Stearate 1 mg (b) 25 mg tablets are prepared from the following composition:

Compound having the General Formula [I] 25 mg Microcrystalline Cellulose 20 mg Lactose mg Starch 23.5 mg Magnesium Stearate 1.5 mg

(c) 10 mg capsules are prepared from the following composition:

The oral daily dose of the compounds having the general formula [I] or a salt thereof for human adults usually ranges from about 0.285 to 2.85 mg per kg of body weight, given in single or divided doses.

In the following illustrative examples of typical and presently preferred embodiments of the invention, g and ml represent grams(s) and milliliter(s), respectively.

EXAMPLE 1 24.6 g of powdery l l-chlorodibenzo[b,f][1,4]thiazepine is added little by little to a mixture of 18.2 g of N-(2-thenyl)piperazine, 15 g of potassium carbonate and 200 ml of benzene, and the resulting mixture is refluxed with vigorous stirring for 5 hours. After cooling, the potassium carbonate is filtered off and the filtrate is concentrated to give 31.7 g of white crystalline l l-[4-(2-thenyl)-l-piperazinyl1- dibenzo[b,f][1,4]thiazepine melting at l07l 10C. This product is suspended in isopropanol and isopropanolic hydrochloric acid is added. 36.4 g of the corresponding dihydrochloride 0.5 hydrate melting at 2082l0C is obtained.

EXAMPLE 2 To a solution of 16.3 g of N-(2-pyridyl)piperazine in 50 ml of pyridine is added slowly with stirring 4.5 g of l l-p-tolylsulfonyloxy-8-trifluoromethyldibenzo[b,f][1,4]thiazepine, and the resulting mixture is stirred at room temperature for 24 hours. The reaction mixture is poured into 500 ml of ice water and the oil separated is extracted with two 200 ml portions of benzene. The benzene extract is dried and then concentrated. The remaining orange-red oil is dissolved in ethanol and ethanolic hydrochloric acid is added. The hydrochloride formed is recrystallized from ethanol to give 27.7 g of 1 l-[4-(2-pyridyl)-l-piperazinyl]-8- trifluoromethyl-dibenzo[b,f][ 1,4]thiazepine dihydrochloride O.5 hydrate melting at 185-l87C.

EXAMPLE 3 A mixture of 37.8 g of ll-p-nitrobenzylthiodibenzo[b,f][l,4]-thiazepine 5,5-dioxide, 36.4 g of N-(2-thenyl)piperazine and lO ml of dioxane is refluxed for hours. The dioxane is distilled off and to the residue is added ethanolic hydrochloric acid. 38.5 g of l l-[4-( 2-thenyl 1 -piperazinyl]-dibenzo [b,f][ l,4]thiazepine 5,5-dioxide dihydrochloride monohydrate melting at l86l89C is obtained.

EXAMPLE 4 A mixture of g of l l-chlorodibenzo[b,f][1,4]thiazepine, 7.2 g of N-benzylpiperazine, 9 g of triethylamine and l 10 ml of toluene is stirred at 85-90 C for 4 hours. After cooling, the reaction mixture is washed with water and dried, and then the solvent is distilled off. The remaining oil is dissolved in ethanol and ethanolic hydrochloric acid is added. 18 g of l l-(4-benzyll -piperazinyl )-dibenzo- [b,f][ 1,4]thiazepine dihydrochloride monohydrate melting at 2l7218C with decomposition (from 90% isopropanol) is obtained.

EXAMPLE 5 To a solution of 7.3 g of N-(o-methylbenzyl)piperazine in 30 ml of pyridine is added slowly 16 g of ll-ptolylsulfonyloxy-dibenzo[b,f][ l,4]-thiazepine and the resulting mixture is stirred at room temperature for 24 hours. The reaction mixture is poured into 500 ml of ice water and the oil separated is extracted with two 200 ml portions of toluene. The toluene extract is dried and concentrated. The remaining product is dissolved in 30 ml of ethanol and ethanolic hydrochloric acid is added. The hydrochloride thus obtained is recrystallized from 50% isopropanol to give 17 g of 1l-[4-(omethylbenzyl)-1-piperaziny1]- dibenzo[b,f][ 1,4]thiazepine dihydrochloride monohydrate melting at 171l73C.

EXAMPLE 6 A mixture of 16 g of ll-p-nitrobenzylthiodibenzo[b,f][ l,4]-thiazepine, 7.8 g of N-(o-methoxyphenyl)piperazine and ml of dioxane is refluxed for 5 hours and then the dioxane is distilled off. To the residue is added ethanolic hydrochloric acid. 13 g of ll-[4-(o-methoxyphenyl)-l-piperazinyl1- dibenzo[b,f][ 1,4]thiazepine dihydrochloride melting at 21 l-212C with decomposition (from isopropanol) is obtained.

EXAMPLE 7 To a mixture of 29.5 g of 11-( l-piperazinyl)- dibenzo[b,f][ l,4]-thiazepine, 200 ml of anhydrous benzene and 27.8 g of potassium carbonate is added dropwise with stirring under cooling 15 g of 2-thenyl chloride. The resulting mixture is stirred at 20C for 12 hours and then refluxed for 3 hours. After cooling, the potassium carbonate is filtered off and the benzene is distilled off. The remaining oil is instantly crystallized and the crystals are recrystallized from isopropanol to give 33.5 g of l 1-[4-(2-thenyl)-l-piperazinyl]- dibenzo[b,f][1,4]thiazepine melting at l07-l 10C. The corresponding hydrochloride 0.5 hydrate melts at 208210C (from 80% isopropanol).

EXAMPLE 8 A solution of 17.7 g of p-chlorobenzyl chloride in 20 ml of tetrahydrofuran is added dropwise with stirring and cooling to a solution of 29.5 g of 11-( lpiperazinyl)-dibenzo[b,f][1,4]thiazepine in ml of pyridine. After stirring at 9095C for 5 hours, the reaction mixture is poured into 500 ml of ice water. The oil separated is extracted with benzene and the benzene extract is washed with water and dried, and then the benzene is distilled off. The remaining oil is dissolved in isopropanol and isopropanolic hydrochloric acid is added. 40 g of ll-[4-(p-chlorobenzyl)-l-piperazinyl1- dibenzo[b,f][ 1,4]thiazepine dihydrochloride monohydrate melting at 232-233C with decomposition (from. 50% isopropanol) is obtained.

EXAMPLE 9 4.8 g of a 50% sodium hydride solution is added to 200 ml of dioxane and 29.5 g of ll-(l-piperazinyl)- -dibenzo[b,f][1,4]thiazepine is added and then the benzene. The benzene extract is dried and concen trated, and than ethanolic hydrochloric acid is added to the oily residue. 32 g of l 1-(4-phenethyl-lpiperazinyl)-dibenzo[b,f][ 1 ,4]thiazepine dihydrochloride monohydrate melting at 270C with decomposition is obtained. I

EXAMPLE 10 To a solution of 29.5 g of 1 l-( l-piperazinyl)- dibenzo[b,f][l,4]-thiazepine in 200 ml of dimethylformamide is added g of potassium carbonate and the whole mixture is stirred. A solution of 30.5 g of o- (p-tolylsulfonyloxymethyl)toluene in 100 ml of dimethylformamide is added dropwise under ice cooling to the mixture. The whole mixture is stirred at room temperature for 15 hours and then heated on a boiling water bath for 5 hours. The dimethylformamide is distilled off and the residue is poured into ice water. The oil separated is extracted with benzene. The benzene extract is washed with water and dried, and then the benzene is distilled off. The remaining oil is dissolved in isopropanol and isopropanolic hydrochloric acid is added. 35.8 g of l l-[4-(o-methylbenzyl)-1-piperazinyl1- dibenzo[b,f][1,4]thiazepine dihydrochloride monohydrate melting at l71l73C with decomposition is obtained.

Using the procedures set forth in above examples, but substituting equivalent amounts of the appropriate starting materials, the following compounds are also produced:

1. 1 l-(4-Furfuryl -piperazinyl)-8-methyldibenzo[b,f][1,4]thiazepine, its dihydrochloride 0.5 hydrate melting at 193196C with decomposition;

2. 8-Chloro-l l-[4-(2-thenyl)- l -piperazinyl]- dibenzo[b,f][1,4]thiazepine, its dihydrochloride melting at 273C;

3. 1 l-[4-(2-thiazolyl)-l l-piperazinyl]- dibenzo[b,f][1,4]thiazepine, its dihydrochloride dihydrate melting at 124C.

4. 2-Chloro-l 1-[4-(2-thenyl)- l -piperazinyl]- dibenzo[b,f][ 1,4]-thiazepine, its hydrochloride melting at 281282C;

5. 1 l-[4-( 2-thenyl)- l -homopiperazinyl dibenzo[b,f][1,4]thiazepine, its dioxalate monohydrate melting at 206207C;

6. 2-Chloro-1 l-[4 (2-thenyl)- l-homopiperazinyl1- dibenzo[b,f][ l ,4]-thiazepine, its dioxalate monohydrate melting at 162163C;

7. l l-[4-(2-( 2-Thienyl)ethyl)- l -piperazinyl]- dibenzo[b,f][1,4]-thiazepine, its trimaleate trihydrate melting at 199200C with decomposition;

8. l l-[4-(2-Pyridylmethyl)-1-piperazinyl]- dibenzo[b,f][1,4]thiazepine, its trihydrochloride 1.5 hydrate melting at 124-l25C;

9. l 1-[4-( 2-( 4-Pyridyl)ethyl l -piperazinyl]- dibenzo[b,f][1,4]-thiazepine, its trihydrochloride 0.5 hydrate melting at 174l76C;

l0. 2-Chloro-l 1-[4-( 2-pyridylmethyl l piperazinyl]-dibenzo[b,f] 1 ,4]-thiazepine, its trihydrochloride 0.5 hydrate melting at 243245C;

1 l. 2-Chloro-1 1-[4-(2-( 4-pyridyl)ethyl)-lpiperazinyl]-dibenzo[b,f][ 1,4]-thiazepine, its trihydrochloride monohydrate melting at 160l61C;

l2. 1l-[4-(2-(2-Pyridyl)ethyl)-l-piperazinyl]- dibenzo[b,f][ 1,41-thiazepine, its trihydrochloride dihydrate melting at 9597C;

13. piperazinyl]-dibenzo[b,f][ 1 ,4]-thiazepine, its trihydrochloride monohydrate melting at 207208C;

14. l 1-[4-( 3-Pyridylmethyl)- 1 -piperazinyl]- dibenzo[b,f][1,4]thiazepine, its trihydrochloride 1.5 hydrate melting at 207208C;

15. Z-Chloro-l l-[4-(3-pyridylmethyl)-lpiperazinyl]-dibenzo[b,f] l ,4]-thiazepine, its trihydrochloride 0.5 hydrate melting at 259260C;

16. l l-[4-(p-chlorobenzyl l -piperazinyl]- dibenzo[b,f][1,4]thiazepine its dihydrochloride monohydrate melting at 232233C with decomposition;

17. l l-[ 4-(m-Trifiuoromethylphenyl l piperazinyl]-dibenzo[b,f][ l ,4]-thiazepine, its dihydrochloride 0.5 hydrate melting at l82l83C with decomposition;

18. l i-[4-(2,5-dichlorophenyl)-1-piperazinyl]- dibenzo[b,f][1,4]-thiazepine, its dihydrochloride melting at 230-232C with decomposition;

19. 1 1 -(4-Benzyl-1 -piperazinyl)-2-chlorodibenzo[b,f][1,4]thiazepine, its hydrochloride melting at 279280C;

20. Z-Chloro-l 1-( 4-phenethyll -piperazinyl)- dibenzo[b,f][1,4]thiazepine, its dihydrochloride dihydrate melting at 17lC;

21 1 l-(4-Benzyll -homopiperazinyl)-2-chlorodibenzo[b,f][1,4]thiazepine, its dioxalate 0.5 hydrate melting at l61l62C;

22. 2-Chloro-[4-(p-chlorobenzyl)-1- homopiperazinyl]-dibenzo[b,f][ l ,4]-thiazepine, its dioxalate melting at 176C;

23. l l-[4-(2-Pyridylmethyl)-l-piperazinyl]- dibenzo[b,f][1,4]thiazepine 5,5dioxide, its dihydrochloride melting at 203204C;

24. 1 1-( 4-Phenethyll -piperazinyl)- dibenzo[b,f][1,4]thiazepine 5 ,5-dioxide, its dihydrochloride 0.5 hydrate melting at above 270C;

25. 1 l-[4-(2-Thenyl)-l-piperazinyH-dibenzo[b,f][l,4]oxazepine, its dihydrochloride melting at l94-196C with decomposition;

26. l l-[4-(2-Thenyl)-1-homopiperazinyl]-dibenzo[b,f][ 1,4]oxazepine, its dihydrochloride 0.5 hydrate melting at 256C with decomposition;

27. Z-Chloro-l l-[4-(2-pyridylmethyl)-1- piperazinyl]-dibenzo[b,f][ 1 ,4]-oxazepine, its trihydrochloride 0.5 hydrate melting at 225-227C;

28. 2-Chloro-l 1-[4-(2-(4-pyridyl)ethyl)-1- piperazinyl]-dibenzo[b,f] l ,4]-oxazepine, its trihydrochloride monohydrate melting at 9698C;

29. 1 l-[4-( 2-Pyridylmethyl)- l -piperazinyl]-dibenzo[b,f][ 1,4]oxazepine, its trihydrochloride dihydrate melting at l96-198C;

30. 1 1-[4-(2-(4-Pyridyl)ethyl)- l-piperazinyl1-dibenzo[b,f][ 1,4]oxazepine its trihydrochloride monohydrate melting at l141 15C;

31. 1 1-[4-(2-(2-Pyridyl)ethyl)-l-piperazinylldibenzo[b,f][1,4]-oxazepine, its trihydrochloride monohydrate melting at 8586C;

32. 2-Chloro-l 1-[4-(2-(2-pyridyl)ethyl)-1- piperazinyl]-dibenzo[b,f][ l ,4]-oxazepine, its trihydrochloride monohydrate melting at 7475C;

33. 1 1-[4-(3-Pyridylmethyl)- 1 -piperazinyl]-dibenzo[b,f][ 1,4]oxazepine, its trihydrochloride monohydrate melting at 235-236C;

34. 2-Chloro-l 1-[4-( 3-pyridylmethyl)- l piperazinyl]-dibenzo[b,f] 1 ,4]-oxazepine, its trihydrochloride O.5 hydrate melting at 255-256C;

35. 1 l-(4-Benzyl-1-piperazinyl)-dibenzo[b,f][ 1 4]oxazepine, its dihydrochloride monohydrate melting at I92199C with decomposition;

36. 1 l-(4-Phenethyl-1-piperazinyl)-dibenzo[b,f][ 1,- 4]oxazepine, its dihydrochloride 1.5 hydrate melting at 234236C;

wherein X is H or Cl, and n is l or 2; or the pharmaceutically acceptable acid addition salts thereof.

2. The compound of claim 1:

1 l-[4-( 2-pyridylmethyl)- l -piperazinyl]-dibenzo [b,f][ 1,4]thiazepine.

3. The compound of claim 1:

1 l-[4-(2-(4-pyridyl)ethyl)- 1-piperazinyl1-dibenzo [b,f][ 1,4]thiazepine.

4. The compound of claim 1:

2-chloro-l 1-[4-(2-pyridylmethyl)-1-piperazinyl1- dibenzo[b,f][ l ,4]thiazepine.

5. The compound of claim 1:

2-chloro-l 1-[4-(2-(4-pyridyl)ethyl)-l-piperazinyl1- dibenzo[b,f][1,4]thiazepine.

6. The compound of claim 1:

l l-[4-( 2-(2-pyridyl )ethyl)- l -piperazinyl]-dibenzo [b,f][ l ,4[thiazepine.

7. The compound of claim 1:

2-chloro-l 1-[4-(2-(2-pyridyl)ethyl)- l-piperazinyl1- dibenzo[b,f][1,4]thiazepine.

8. The compound of claim 1:

l l-[4-( 3-pyridylmethyl 1 -piperazinyl]-dibenzo [b,f][ 1,4]thiazepine.

9. The compound of claim 1:

2-chloro-l l-[4-( 3-pyridylmethyl l -piperazinyl]- dibenzo[b,f][ 1,4]thiazepine. 

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1: 11-(4-(2-pyridylmethyl)-1-piperazinyl)-dibenzo (b,f)(1, 4)thiazepine.
 3. The compound of claim 1: 11-(4-(2-(4-pyridyl)ethyl)-1-piperazinyl)-dibenzo (b,f)(1, 4)thiazepine.
 4. The compound of claim 1: 2-chloro-11-(4-(2-pyridylmethyl)-1-piperazinyl)-dibenzo(b,f)(1, 4)thiazepine.
 5. The compound of claim 1: 2-chloro-11-(4-(2-(4-pyridyl)ethyl)-1-piperazinyl)-dibenzo(b, f)(1,4)thiazepine.
 6. The compound of claim 1: 11-(4-(2-(2-pyridyl)ethyl)-1-piperazinyl)-dibenzo (b,f)(1, 4(thiazepine.
 7. The compound of claim 1: 2-chloro-11-(4-(2-(2-pyridyl)ethyl)-1-piperazinyl)-dibenzo(b, f)(1,4)thiazepine.
 8. The compound of claim 1: 11-(4-(3-pyridylmethyl)-1-piperazinyl)-dibenzo (b,f)(1, 4)thiazepine.
 9. The compound of claim 1: 2-chloro-11-(4-(3-pyridylmethyl)-1-piperazinyl)-dibenzo(b,f)(1, 4)thiazepine. 